Stabilized pharmaceutical composition

ABSTRACT

The pharmaceutical composition of the invention, which comprises a benzimidazole compound of the formula                    
     wherein R 1  is hydrogen, alkyl, halogen, cyano, carboxy, carboalkoxy, carboalkoxyalkyl, carbamoyl, carbamoylalkyl, hydroxy, alkoxy, hydroxyalkyl, trifluoromethyl, acyl, carbamoyloxy, nitro, acyloxy, aryl, aryloxy, alkylthio or alkylsulfinyl, R 2  is hydrogen, alkyl, acyl, carboalkoxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, alkylcarbonylmethyl, alkoxycarbonylmethyl or alkylsulfonyl, R 3  and R 5  are the same or different and each is hydrogen, alkyl, alkoxy or alkoxyalkoxy, R 4  is hydrogen, alkyl, alkoxy which may optionally be fluorinated, or alkoxyalkoxy, and m is an integer of 0 through 4, and a basic inorganic salt stabilizing agent, is physically stable. Magnesium and calcium basic inorganic salt stabilizing agents are particularly useful.

This application is a Divisional of application Ser. No. 10/079,958,filed on Feb. 19, 2002, now U.S. Pat. No. 6,521,256 which is aDivisional of application Ser. No. 09/924,234, filed Aug. 8, 2001, nowU.S. Pat. No. 6,380,234 which is a Divisional of application Ser. No.09/588,956, filed Jun. 7, 2000 (now a US Pat. No. 6,296,875) which is aDivisional of application Ser. No. 09/429,957, filed Oct. 29, 1999 (nowU.S Pat. No. 6,123,962), which is a Divisional of application Ser. No.09/196,664, filed Nov. 19, 1998 (now U.S. Pat. No. 6,017,560) which is acontinuation of application Ser. No. 08/810,951, filed Feb. 27, 1997(now U.S. Pat. No. 5,879,708), which is a continuation of Ser. No.08/488,152, filed Jun. 7, 1995 (now U.S. Pat. No. 5,639,478), which is acontinuation of Ser. No. 08/120,867, filed on Sep. 10, 1993 (now U.S.Pat. No. 5,433,959), which is a continuation of Ser. No. 07/793,091,filed Nov. 15, 1991 (now abandoned), which is a divisional of Ser. No,07/575,897, filed Aug. 31, 1990 (now U.S. Pat. No. 5,093,132), which isa continuation of Ser. No. 07/014,303, filed Feb. 13, 1987 (now U.S.Pat. No. 5,045,321) which application(s) are incorporated herein byreference.

This invention relates to a pharmaceutical-composition which comprises2-[(2-pyridyl)methylsulphinyl]benzimidazole or a derivative thereof(hereinafter sometimes referred to collectively as “benzimidazolecompounds”), particularly the derivatives2-[[3-methyl-4-(2,2,2-trifluoromethoxy)-2-pyridyl]methylsulfinyl]benzimidazoleand5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]benzimidazole,or a pharmaceutically acceptable salt thereof, which is useful as anantiulcer agent. The composition is stabilized by incorporation of aneffective amount of a basic inorganic salt stabilizing agent, with basicinorganic salts of magnesium, calcium, potassium and sodium beinguseful, the magnesium can calcium salts being preferred.

Certain benzimidazole compounds are recently under clinical study asgastric acid secretion inhibitors. They serve as therapeutic agents fordigestive ulcer. Their principal pharmacological effect consists ingastric acid secretion suppression based on (H⁺+K⁺)-ATPase inhibitionand is more potent and durable as compared with histamine H₂ receptorantagonists such as cimetidine and ranitidine. They also have gastricmucosa protecting activity. Therefore, they have attracted attention asnext-generation potent therapeutic agents for digestive ulcer.

Those benzimidazole compounds which are described in Japanese UnexaminedPatent laid open Nos. 62275/77, 141783/79, 33406/82, 135881/83,192880/83 and 181277/84, corresponding to U.S. Pat. No. 4,045,563, U.S.Pat. No. 4,275,431, European Patent Publication No. 45,200, U.S. Pat.No. 4,472,409, European Patent Publication No. 5,129 and G.B. PatentPublication No. 2,134,523A, respectively, among others are known to haveantiulcer activity.

These compounds, however, are poor in stability. In solid state, theyare susceptible to heat, moisture and light and, in aqueous solution orsuspension, their stability decreases with decreasing pH. In dosageforms, i.e. tablets, powders, fine granules, granules and capsules, saidcompounds are apt to interact with other components contained in saiddosage forms and accordingly are in less stable state as compared withthe case where they occur alone. Thus, the content decreases and thecolor changes significantly in the manufacturing process of dosage formand with the lapse of time. Microcrystalline cellulose,polyvinylpyrrolidone (PVP), carboxymethylcellulose calcium, polyethyleneglycol 6000 and Pluronic F68 (polyoxyethylene-polyoxypropylenecopolymer), for instance are dosage form components adversely affectingthe stability of said compounds. Furthermore, in the case of coatedtablets and coated granules among the above dosage forms, entericcoating bases such as cellulose acetate phthalate,hydroxy-propylmethylcellulose acetate succinate and Eudragit(methacrylic acid-acrylic acid copolymer) have poor compatibility withsaid compounds and cause content decrease and color change.Nevertheless, one or more of these components or ingredients, which, asmentioned above, can produce adverse effects on the stability of saidcompounds, are essential in the manufacture of oral preparations andtherefore difficulties are inevitably encountered in dosage formmanufacture.

The prior art avoids the above-mentioned stability problem by using saidbenzimidazole compounds in a salt form, say in the form of a lithium,sodium, Potassium, magnesium, calcium or titanium salt [JapaneseUnexamined Patent laid open No. 167587/84 (European Patent PublicationNo. 124,495A)]

However, the above prior art method requires, for the stabilization ofthe benzimidazole compounds, a step of converting said compounds to sucha salt form as mentioned above in advance.

In view of the above, the present inventors made investigations in anattempt to stabilize pharmaceutical preparations containingbenzimidazole compounds and, as a result, have completed the presentinvention.

Thus, this invention relates to

(1) A pharmaceutical composition which comprises2-[(2-pyridyl)methylsulfinyl]benzimidazole or a derivative thereof,which has an antiulcer activity, and a basic inorganic salt of magnesiumand/or a basic inorganic salt of calcium, and

(2) A method of producing a stabilized pharmaceutical composition whichcomprises incorporating a basic inorganic salt of magnesium and/or abasic inorganic salt of calcium in a pharmaceutical compositioncontaining 2-[(2-pyridyl-methylsulfinyl]benzimidazole or a derivativethereof, which has an antiulcer activity.

The benzimidazole compounds having an antiulcer activity which are to beused in the practice of the invention are those compounds which aredescribed in the above-cited laid-open patent specifications, forinstance and are represented by the formula

wherein R¹ is hydrogen, alkyl, halogen, cyano, carboxy, carboalkoxy,carboalkoxyalkyl, carbamoyl, carbamoylalkyl, hydroxy, alkoxy,hydroxyalkyl, trifluoromethyl, acyl, carbamoyloxy, nitro, acyloxy, aryl,aryloxy, alkylthio or alkylsulfinyl, R² is hydrogen, alkyl, acyl,carboalkoxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,alkylcarbonylmethyl, alkoxycarbonylmethyl or alkylsulfonyl, R³ and R⁵are the same or different and each is hydrogen, alkyl, alkoxy oralkoxyalkoxy, R⁴ is hydrogen, alkyl, alkoxy which may optionally befluorinated, or alkoxyalkoxy, and m is an integer of 0 through 4.

The compounds of the formula(I) can be produced by the methods describedin the above-cited laid-open patent specifications or modificationsthereof.

In the following, brief mention is made of the substituents in thosecompounds which have the formula (I) and are already known.

Referring to R¹ in the above formula, C₁₋₇ alkyls may be mentioned asthe alkyl represented by R¹; C₁₋₄ alkoxys as the alkoxy moiety of thecarboalkoxy; C₁₋₄ alkoxys as the alkoxy moiety of the carboalkoxyalkyland C₁₋₄ alkyls as the alkyl moiety; C₁₋₄ alkyls as the alkyl moiety ofthe carbamoylalkyl; C₁₋₅ alkoxys as the alkoxy; C₁₋₇ alkyls as the alkylmoiety of the hydroxyalkyl; C₁₋₄ alkanoyls as the acyl; phenyl as thearyl; phenyl as the aryl moiety of the aryloxy; C₁₋₆ alkyls as the alkylmoiety of the alkylthio; and C₁₋₆ alkyls as the alkyl moiety of thealkylsulfinyl.

Referring to R², C₁₋₅ alkyls may be mentioned as the alkyl representedby R²; C₁₋₄ alkanoyls as the acyl; C₁₋₄ alkoxys as the alkoxy moiety ofthe carboalkoxy; C₁₋₄ alkyls as the alkyl moiety of the alkylcarbamoyl;C₁₋₄ alkyls as each of the alkyl moieties of the dialkylcarbamoyl; C₁₋₄alkyls as the alkyl moiety of the alkylcarbonylmethyl; C₁₋₄ alkoxys asthe alkoxy moiety of the alkoxycarbonylmethyl; and C₁₋₄ alkyls as thealkyl moiety of the alkylsulfonyl.

Referrring to R³, R⁴ and R⁵, C₁₋₄ alkyls may be mentioned as the alkylrepresented by any of them; C₁₋₈ alkoxys as the alkoxy; and C₁₋₄ alkoxysas each of the alkoxy moieties of the alkoxyalkoxy.

Referring to R⁴, C₁₋₈ alkoxys may be mentioned as the alkoxy, which mayoptionally be fluorinated.

Among those compounds of the above formula (I), (1) the compounds ofwhich R¹ is hydrogen, methoxy or trifluoromethyl, R² is hydrogen, R³ andR⁵ are the same or different and each is hydrogen or methyl, R⁴ isfluorinated C₂₋₅ alkoxy and m is 1, (2) the compounds of which R¹ ishydrogen, fluorine, methoxy or trifluoromethyl, R² is hydrogen, R³ ishydrogen or methyl, R⁴ is C₃₋₈ alkoxy, R⁵ is hydrogen and m is 1, and(3) the compounds of which R¹ is hydrogen, fluorine, methoxy ortrifluoromethyl. R² is hydrogen, R³ is C₁₋₈ alkoxy, R⁴ is C₁₋₈ alkoxywhich may be fluorinated, R⁵ is hydrogen and m is 1.

Detailed mention is now made of the substituents in such novelcompounds.

Referring to R³, the lower alkyl represented thereby is preferably C₁₋₈lower alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, pentyloxy, hexyloxy, heptyloxy or octyloxy and morepreferably C₁₋₄ lower alkoxy.

Referring to R⁴, C₁₋₈ lower alkoxys may be mentioned as the loweralkoxy, which may optionally be fluorinated, and preferred examples areas mentioned above for R³. As the fluorinated lower alkoxy, there may bementioned, for example, 2,2,2-trifluoroethoxy,2,2,3,3,3-pentafluoropropoxy, i-(trifluoromethyl)-2,2,2-trifluoroethoxy,2,2,3,3-tetrafluoropropoxy, 2,2,3,3,4,4,4-heptafluorobutoxy and2,2,3,3,4,4,5,5-octafluoropentoxy, and fluorinated C₂₋₄ lower alkoxysare preferred.

The position or R¹ is position 4 or position 5, preferably position 5.

Some methods of producing the above novel compounds [hereinafterreferred to as “compounds or Formula (I′)”] are described below.

Said compounds can be produced by subjecting a compound of the formula

wherein R¹-R⁵ are as defined above, to oxidation.

The oxidizing agent to be used is, for example, meta-chloroperbenzoicacid, peracetic acid, trifluoroperacetic acid, permaleic acid or thelike peracid, sodium bromite or sodium hypochlorite. Examples of thesolvent to be used in carrying out the reaction are halogenatedhydrocarbons such as chloroform and dichloromethane, ethers such astetrahydrofuran and dioxane, amides such as dimethylformaide, and water.These solvents may be used either singly or in admixture. Said oxidizingagent is used preferably in an amount approximately equivalent orslightly excessive relative to the compound (II). Thus, said agent isused in an amount of about 1-3 equivalents, more preferably about 1 to1.5 equivalents. The reaction is carried out at a temperature from about0° C. (ice cooling) to around the boiling point of the solvent used,generally at a temperature from about 0° C. (ice cooling) to roomtemperature, preferably at a temperature of about 0° C. to 10° C. Thereaction time is generally about 0.1 to 24 hours, preferably about 0.1to 4 hours.

The desired novel compounds (I′) produced by the above reaction can beisolated and purified by conventional means such as recrystallization,chromatography and so on.

Said compounds may be converted to pharmacologically acceptable salts byconventional means. As such salts, there may be mentioned hydrochloride,hydrobromide, hydroiodide, phosphate, nitrate, sulfate, acetate andcitrate, among others.

The novel compounds (II) can be produced by reacting a starting compoundof the formula

wherein R¹ and R² are as defined above, with a starting compound of theFormula

wherein R³-R⁵ are as defined above and X is a halogen atom.

The halogen atom represented by X is, for example, chlorine, bromine oriodine.

The reaction is carried out advantageously in the presence of a base. Assaid base, there may be mentioned alkali metal hydrides such as sodiumhydride and potassium hydride, alkali metals such as metallic sodium,sodium alcoholates such as sodium methoxide and sodium ethoxide, alkalimetal carbonates such as potassium carbonate and sodium carbonate, andorganic amines such as triethylamine, among others. As the solvent to beused in carrying out the reaction, there may be mentioned, for example,alcohols such as methanol and ethanol, and dimethylformamide. The baseis used generally in an amount slightly excessive relative to theequivalent amount but may also be used in large excess. Thus, it is usedin an amount of about 2-10 equivalents, preferably about 2-4equivalents. The above reaction is carried out generally at atemperature of about 0° C. to around the boiling point of the solventused, preferably at about 20° C. to 80° C., for a period of about 0.2-24hours, preferably about 0.5-2 hours.

Some methods of producing the starting compounds (IV) are describedbelow.

Among the compounds (IV), those compounds wherein R³ and R⁵ are the sameor different and each is hydrogen or methyl and R⁴ is fluorinated C₂₋₅alkoxy or C₃₋₈ alkoxy can be produced by the following process:

A nitro compound of the formula (V) , wherein R³ and R⁵ are as definedabove, is reacted with an alcohol derivative of the formula R^(4′) OH(VI) wherein R^(4′) is fluorinated C₂₋₅ alkyl or C₃₋₈ alkyl, in thepresence of a base to give an alkoxy derivative of the formula (VII)wherein R³, R⁴ and R⁵ are as defined above. The base to be used incarrying out the reaction includes, among others, alkali metals such aslithium, sodium and potassium, alkali metal hydrides such as sodiumhydride and potassium hydride, alcoholates such as potassium t-butoxideand sodium propoxide, alkali metal carbonates and hydrogen carbonatessuch as potassium carbonate, lithium carbonate, sodium carbonate,potassium hydrogen carbonate and sodium hydrogen carbonate, and alkalimetal hydroxides such as sodium hydroxide and potassium hydroxide. Thealcohol derivative to be submitted to the reaction includes, amongothers, propanol, isopronanol, butanol, pentanol, hexanol,2,2,2-trifluoroethanol, 2,2,3,3,3-pentafluoropropanol,2,2,3,3-tetrafluoropropanol, 1-(trifluoromethyl)-2,2,2-trifluoroethanol,2,2,3,3,4,4,4-heptafluorobutanol and 2,2,3,3,4,4,5,5-octafluoropentanol.While R^(4′) OH itself may be used as a solvent in carrying out thereaction, ethers such as tetrahydrofuran and dioxane, ketones such asacetone and methyl ethyl ketone, acetonitrile, dimethylformamide andhexamethylphosphoric acid triamide, for instance, may also be used assolvents. An appropriate reaction temperature may be selected within therange or about 0° C. (ice cooling) to around the boiling point of thesolvent used. The reaction time is about 1-48 hours;

Heating (about 80-120° C.) of the thus-obtained compound (VII) withacetic anhydride alone or in the presence of an inorganic acid such assulfuric acid or perchloric acid gives an 2-acetoxymethylpyridinederivative of the formula (VIII) wherein R³, R⁴ and R⁵ are as definedabove. The reaction period is generally about 0.1-10 hours.

The subsequent alkaline hydrolysis of the compound (VIII) gives a2-hydroxymethyloyridine derivative of the formula (IX). Sodiumhydroxide, potassium hydroxide, potassium carbonate and sodiumcarbonate, for instance, are usable as alkalis, and methanol, ethanoland water, among others, are usable as solvents. The reaction isgenerally conducted at about 20-60° C. for about 0.1-2 hours.

The compound (IX) is further halogenated with a chlorinating agent suchas thionyl chloride to give a 2-halomethylpyridine derivative of theformula (IV) wherein R³, R⁴ and R⁵ are as defined above and X ischlorine, bromine or iodine. Usable as solvents are, for example,chloroform, dichloromethane and tetrachloroethane. The reaction isgenerally carried out at about 20-80° C. for about 0.1-2 hours.

The compound (IV) thus produced occurs in the form of a salt ofhydrohalogenic acid corresponding to the halogenating agent used and itis generally preferable to subject said compound to reaction with thecompound (III) immediately.

Among the compounds (V), those compounds wherein R³ is C₁₋₈ a loweralkoxy, R⁴ is alkoxy which may optionally be fluorinated, and R⁵ ishydrogen can be produced by the following process 2)

Thus, maltol (X) is reacted with a alkyl halide of the formula R^(3′) Xin the presence of sliver oxide, for instance, to give a compound of theformula (XI). Reaction of (XI) with aqueous ammonia gives a pyridonederivative of the formula (XII). Direct alkylation of the compound (XII)with an alkyl halide, or halogenation of (XII) with a halogenating agentsuch as phosphorus oxychloride followed by reaction of the resultanthalo derivative (XIV) with a lower alcohol of the formula R^(4″) OH inthe presence of a base gives a compound of the formula (XIII). Thecompound (XIII) can be converted to the compound (IV) by directhalogenation with N-bromosuccinimide or chlorine, for instance. Thecompound (XIII) may also be converted to the compound (IV) by oxidizingthe same with an oxidizing agent such as m-chloroperbenzoic acid,reacting the resulting compound (XV) with acetic anhydride, hydrolyzingthe resulting compound (XVI) and halogenating the resulting compound(XVII) with a halogenating agent such as thionyl chloride.

The alkyl halide to be used in the production of the compound (XI)includes, among others, methyl iodide, ethyl iodide, propyl iodide,isopropyl iodide, butyl iodide, pentyl iodide and hexyl iodide, and thealkyl halide to be used in the production of the compound (XIII) furtherincludes, in addition to those mentioned above for use in the productionof the compounds (XI), 2,2,2-trifluoroethyl iodide,2,2,3,3,3-pentafluoropropyl iodide, 2,2,3,3-terrafluoropropyl iodide,1-(trifluoromethyl)-2,2,2-trifluoroethyl iodide,2,2,3,3,4,4,4-heptafluorobutyl iodide, and2,2,3,3,4,4,5,5-octafluoropentyl iodide, for instance. Such alkyliodides are used in an amount of about 1-10 equivalents. Silver oxide,potassium carbonate, sodium carbonate or the like is used as adeacidifying agent and dimethylformamide, dimethylacetamide or the likeis used as a solvent. The reaction is generally carried out at roomtemperature.

The halogenating agent to be used in the production of the compound(XIV) includes, among others, phosphorus oxychloride, phosphoruspentoxide and phosphorus tribromide and is used in an amount of 1equivalent to a large excess. The reaction is carried out at atemperature of about 50-150° C. The alcohol to be used for theconversion of compound (XIV) to compound (XIII) includes methanol andethanol and further those alcohol derivaitves mentioned for use inprocess 1) and is used in an amount of 1 equivalent to a large excess,and the base includes those sodium alcoholates and potassium alcoholateswhich correspong to the respective alcohols as well as potassiumt-butoxide, sodium hydride and so forth. An appropriate reactiontemperature may be selected within the range of room temperature to theboiling point of the solvent used.

For direct bromination of the compound (XIII) with N-bromosuccinimide,the reaction is preferably carried out under light irradiation, andcarbon tetrachloride, chloroform, tetrachloroethane or the like is usedas a solvent.

The oxidizing agent to be used for the conversion of compound (XIII) tocompound (XV) includes, among others, peracids such asmeta-chloroperbenzoic acid, peracetic acid, trifluoroperacetic acid andpermaleic acid as well as hydrogen peroxide. Usable as solvents for thereaction are halogenated hydrocarbons such as chloroform anddichloromethane, ethers such as tetrahydrofuran and dioxane, amides suchas dimethylformamide, acetic acid and water, for instance, and these canbe used either singly or in admixture. Said oxidizing agent ispreferably used in an amount of about 1 equivalent to an excess relativeto the compound (XIII), more preferably about 1-10 equivalents. Thereaction is carried out at a temperature of about 0° C. (ice cooling) toaround the boiling point of the solvent used generally for a period ofabout 0.1-24 hours, preferably for about 0.1-4 hours.

The conversion of compound (XV) to compound (XVI) is effected by heating(at about 80-120° C.) the compound (XV) with acetic anhydride alone orin the presence of an inorganic acid such as sulfuric acid or perchloricacid and so on. The reaction period is generally 0.1-10 hours.

The alkali to be used in the alkaline hydrolysis of compound (XVI) tocompound (XVII) includes, among others, sodium hydroxide, potassiumhydroxide, potassium carbonate and sodium carbonate. Methanol, ethanoland water, for instance, may be mentioned as usable solvents. Thereaction is generally carried out at a temperature of about 20-60° C.for a period of about 0.1-2 hours.

For the production of compound (IV) from compound (XVII), a chlorinatingagent such as thionyl chloride or an organic sulfonic or organicphosphoric acid chloride such as methanesulfonyl chloride,p-toluenesulfonyl chloride or diphenylphosphoryl chloride is used. Whena chlorinating agent such as thionyl chloride is used, it is used in anamount of 1 equivalent to a large excess relative to the compound (XVII)and a solvent such as chloroform, dichloromethane or tetrachloroethaneis used, and the reaction is generally carried out at a temperature ofabout 20-80° C. for a period of about 0.1-2 hours. When an organicsulfonic or organic phosphoric acid chloride is used, is,is used in anamount of 1 equivalent to a slight excess relative to the compound(XVII) and the reaction is generally carried out in the presence of abase. As usable bases, there may be mentioned organic bases such astriethylamine and tributylamine and inorganic bases such as sodiumcarbonate, potassium carbonate and sodium hydrogen carbonate. The baseis used in an amount of 1 equivalent to a slight excess. As usablesolvents, there may be mentioned, for example, chloroform,dichloromethane, carbon tetrachloride and acetonitrile. An appropriatereaction temperature and an appropriate reaction can be selected withinthe ranges of about 0° C. (ice cooling) to around the boiling point andseveral minutes to several hours, respectively.

The above-mentioned novel benzimidazole compounds have excellent gastricantisecretory activity, gastric mucosa-protecting activity and antiulceractivity but have low toxicity, so that they can be used in thetreatment of digestive ulcers in mammals (e.g. mouse, rat, rabbit, dog,cat, human).

The basic inorganic salt stabilizing agents, which are to be used inaccordance with the invention, are now described.

Especially useful basic inorganic salt stabilizing agents are basicinorganic salts of magnesium and calcium. Said basic inorganic salt ofmagnesium includes, among others, heavy magnesium carbonate, magnesiumcarbonate, magnesium oxide, magnesium hydroxide, magnesium metasilicatealuminate, magnesium silicate aluminate, magnesium silicate, magnesiumaluminate, synthetic hydrotalcite [Mg₆Al₂(OH)₁₆.CO₃ .4H₂O] and aluminummagnesium hydroxide [2.5 MgO.Al₂O₃.xH₂O] and said basic inorganic saltof calcium includes, among others, precipitated calcium carbonate andcalcium hydroxide. Other basic inorganic salts useful as stabilizingagents include sodium and potassium basic inorganic salts such aspotassium carbonate, sodium carbonate and sodium hydrogen carbonate, aswell as aluminum basic inorganic salts such as aluminum silicate. It isonly required of such basic inorganic salts to show basicity (pH of notless than 7) when they are in the form of a 1% aqueous solution orsuspension.

Said basic inorganic salts may be used either singly or in combinationof two or more species in an amount which may vary depending on thekinds thereof but generally lies within the range of about 0.3-20 partsby weight, preferably about 0.6-7 parts by weight, per part by weight ofthe benzimidazole compounds.

the composition of the invention may further contain such additives asvehicles (e.g. lactose, corn starch, light silicic anhydride,microcrystalline cellulose, sucrose), binders (e.g. α-form starch,methylcellulose, carboxymethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, polyvinylpyrrolidone), disintegratingagents (e.g. carboxymethylcellulose calcium, starch, low substitutedhydroxypropylcellulose), surfactants [e.g. Tween 80 (Kao-Atlas),Pluronic F68 (Asahi Denke; polyoxyethylene-polyoxypropylene copolymer],antioxidants (e.g. L-cysteine, sodium sulfite, sodium ascorbate),lubricants (e.g. magnesium stearate, talc), etc.

The composition of the invention is prepared by homogeneously admixingthe above benzimidazole compound, the basic inorganic salt stabilizingagent, and the above additives.

The particle sizes of said benzimidazole compound and said inorganicsalt are not especially critical in a condition that they can behomogeneously admixed. For example, preferable perticle size is aboutless than 100 μm, more preferable one is about less than 20 μm.

The moisture amount in the composition is preferably about 6-60%, morepreferably about 20-40% as equibrium relative humidity (E.R.H.). Themethod of admixing is optional if the benzimidazole compound can finallybe in contact with the basic inorganic salt stabilizing agent evenly.Thus, for example, the additives may be admixed with a mixture of thebenzimidazole compound and the basic inorganic salt stabilizing agent asprepared by preliminary admixing, or the basic inorganic saltstabilizing agent may be added to a mixture of the benzimidazolecompound and the additives as prepared by preliminary admixing.

Said mixture can be made up into dosage forms suited for oraladministration, such as tablets, capsules, powders, granules and finegranules, by per se known means.

Tablets, granules and fine granules may be coated by a per se knownmethod for the purpose of masking of the taste or providing them withenteric or sustained release property. Usable as coating agents are, forexample, hydroxypropylmethylcellulose, ethylcellulose,hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol,Tween 80, Pluornic F68, cellulose acetate phthalate,hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetatesuccinate, Eudragit (Röhm, West Germany; methacrylic acid-acrylic acidcopolymer) and pigments such as titanium oxide and ferric oxide.

Tablets, granules, powders, fine granules and capsules can be producedby a conventional method (e.g. the method described in the 10th editionof the Japanese Pharmacopeia under General Rules for Preparations).Thus, for example, tablets are produced by adding the basic inorganicsalt stabilizing agent to a mixture of the benzimidazole compound,vehicle and disintegrant, mixing, adding a binder, granulating themixture, adding a lubricant etc. and tableting the resultant granularcomposition. Granules are produced by extrusion in approximately thesame manner as in the production of tablets or by coating nonpareils,which contain sucrose and corn starch, with a mixture of benzimidazolecompound, a basic inorganic salt stabilizing agent, and additives (e.g.sucrose, corn starch, crystalline cellulose, hydroxypropyl-cellulose,methylcellulose, hydroxypropylmethyl-cellulose, polyvinylpyrrolidone)Capsules are produced by mere mixing and filling. The dosage forms thusobtained show excellent stability with slight changes in appearance andlittle decreases in content even after storage for a long period oftime.

The pharmaceutical composition of the present invention as obtained inthe above manner exhibits excellent gastric antisecretory, gastricmucosa-protecting and antiulcer activities and has low toxicity andtherefore can be used in the treatment of digestive ulcers in mammals(e.g. mouse, rat, rabbit, dog, cat, pig, human).

The pharmaceutical composition of the invention can be orallyadministered for the treatment of digestive ulcers in mammals inadmixture with pharmacologically acceptable carriers, vehicles, diluentsand so forth and in the form of capsules, tablets, granules and someother dosage forms, as mentioned hereinabove. The dose as thebenzimidazole compound lies within the range of about 0.01 mg to 30mg/kg/day, preferably about 0.1 mg to 3 mg/kg/day.

The following reference examples and working examples as well as theexperimental examples described later herein illustrate the presentinvention in more detail but are by no means limitative of the presentinvention.

REFERENCE EXAMPLE 1

A mixture of 2,3-dimethyl-4-nitropyridine-1-oxide (2.0 g), methyl ethylketone (30 ml), 2,2,3,3,3-pentafluoropropanol (3.05 ml), anhydrouspotassium carbonate (3.29 g) and hexamethylphosphoric acid triamide(2.07 g) was heated at 70-80° C. with stirring for 4.5 days. Then, theinsoluble matter was filtered off and the filtrate was concentrated.Water was added to the residue and the mixture was extracted with ethylacetate. The extract layer was dried over magnesium sulfate, then thesolvent was distilled off, and the residue was applied to a silica gelcolumn (50 g). Elution with chloroform-methanol (10:1) andrecrystallization from ethyl acetate-hexane gave 2.4 g of2,3-dimethyl-4-(2,2,3,3,3-pentafluoropropoxy)pyridine-1-oxide ascolorless needles. Melting point 148-149° C.

The following compounds (VII) were produced from the correspondingcompounds (V) in the same manner as above.

Compounds (VII) R³ R⁵ R⁴ Melting point (° C.) CH₃ H OCH₂CF₃ 131.0-131.5Note 1) H H OCH₂CH₂CH₃ Oil Note 2) CH₃ H OCH₂CH₂CH₃ Oil Note 1): NMRspectrum (CDCl₃) δ: 1.01 (3H, t, J = 7 Hz), 1.81 (2H, m), 2.50 (3H, s),3.93 (2H, t, J = 7 Hz), 6.50-6.80 (2H, m), 8.10 (1H, d, J = 7 Hz) Note2): NMR spectrum (CDCl₃) δ: 1.07 (3H, t, J = 7.5 Hz), 1.65-2.02 (2H, m),2.21 (3H, s), 2.52 (3H, s), 3.99 (2H, t, J = 6 Hz), 6.68 (1H, d, J = 6Hz), 8.15 (1H, d, J = 6 Hz)

REFERENCE EXAMPLE 2

Concentrated sulfuric acid (2 drops) was added to a solution or2,3-dimethyl-4-(2,2,3,3,3-pentafluoropropoxy)-pyridine-1-oxide (2.5 g)in acetic anhydride (8 ml) and the mixture was stirred at 110° C. for 2hours and then concentrated. The residue was dissolved in methanol (30ml), 2 N aqueous sodium hydroxide (20 ml) was added, and the mixture wasstirred at room temperature for 2 hours. After concentration, water wasadded to the residue and the mixture was extracted with ethyl acetate.The extract was dried over magnesium sulfate, the solvent was thendistilled off, and the residue was applied to a silica gel (50 g)column. Elution with chloroform-methanol (10:1) and recrystallizationfrom isopropyl ether gave 1.6 g of2-hydroxymethyl-3-methyl-4-(2,2,3,3,3-pentafluoropropoxy)-pyridine as abrown oil.

NMR spectrum (CDCl₃) δ: 2.07 (3H, s), 4.28 (1H, brs), 4.49 (2H, t, J=12Hz), 4.67 (2H, s), 6.69 (1H, d, J=5 Hz), 8.34 (1H, d, J=5 Hz)

The following compounds (IX) were produced from the correspondingcompounds (VII) in the same manner as mentioned above.

Compounds (IX) R³ R⁵ R⁴ Melting point (° C.) CH₃ H OCH₂CF₃ 93.5-94.0Note 1) H H OCH₂CH₂CH₃ Oil Note 2) CH₃ H OCH₂CH₂CH₃ Oil Note 1) NMRspectrum (CDCl₃) δ: 1.0 (3H, t, J = 7.5 Hz), 1.79 (2H, m), 3.92 (2H, t,J = 6 Hz), 4.51-4.90 1H, br), 4.68 (2H, s), 6.68 (1H, dd, J = 2 and 6Hz), 6.80 (1H, d, J = 2 Hz), 8.28 (1H, d, J = 6 Hz) Note 2) NMR spectrum(CDCl₃) δ: 1.03 (3H, t, J = 7.5 Hz), 1.82 (2H, m), 2.02 (3H, s), 3.95(2H, t, J = 6 Hz), 4.62 (2H, s), 5.20 (1H, brd, s), 6.68 (1H, d, J = 6Hz), 8.25 (1H, d, J = 6 Hz)

REFERENCE EXAMPLE 3

Thionyl chloride (0.2 ml) was added to a solution of2-hydroxymethyl-3-methyl-4-(2,2,3,3,3-pentafluoropropoxy)-pyridine (350mg) in chloroform (10 ml) and the mixture was refluxed for 30 minutesand then concentrated. The residue was dissolved in methanol (5 ml) andthe solution was added to a mixture of 2-mercaptobenzimidazole (200 mg),28% sodium methoxide solution (1 ml) and methanol (6 ml). The resultantmixture was refluxed for 30 minutes. The methanol was distilled off,water was added to the residue, and the mixture was extracted with ethylacetate. The extract was washed with dilute sodium hydroxide solutionand cried over magnesium sulfate. The solvent was then distilled off,and the residue was applied to a silica gel (20 g) column. Elution withethyl acetate-hexane (2:1) and recrystallization from ethylacetate-hexane gave 370 mg of2-[[(3-methyl-4-(2,2,3,3,3-pentafluoropropoxy)-2-pyridyl]-methylthio]benzimidazolehemihydrate as colorless plates. Melting point 145-146° C.

The following compounds (II) were produced by reacting the compound(III) with the corresponding compound (IV) in the same manner asmentioned above.

Compounds (II) R¹ R² R³ R⁵ R⁴ Melting point (° C.) H H CH₃ H OCH₂CF₃149-150 H H H H OCH₂CH₂CH₃ 84-86 Note) H H CH₃ H OCH₂CH₂CH₃ Oil Note)NMR spectrum (CDCl₃) δ: 0.98 (3H, t, J = 7.5 Hz), 1.54-1.92 (2H, m),2.15 (3H, s), 3.80 (2H, t, J = 6 Hz), 4.43 (2H, s), 6.55 (1H, d, J = 6Hz), 7.09 (2H, m), 7.50 (2H, m), 8.21 (1H, d, J = 6 Hz)

REFERENCE EXAMPLE 4

A solution of m-chloroperbenzoic acid (1.3 g) in chloroform (15 ml) wasadded dropwise to a solution of2-[[(3-methyl-4-(2,2,3,3,3-pentafuloropropoxy)-2-pyridyl]-methylthio]benzimidazole(2.2 g) in chloroform (20 ml) with ice cooling over 30 minutes and,then, the reaction mixture was washed with saturated aqueous sodiumhydrogen carbonate solution, dried over magnesium sulfate andconcentrated. The concentrate was applied to a silica gel (50 g) column.Elution with ethyl acetate and recrystallization from acetone-isopropylether gave 1.78 g of2-[[3-methyl-4-(2,2,3,3,3-pentafluoropropoxy)-2-pyridyl]methyl-sulfinyl]benzimidazole[hereinafter sometimes referred to as compound (A)] as pale yellowprisms. Melting point 161-163° C. (decomposition).

The following compounds (I) [hereinafter sometimes referred to ascompound (B), compound (C) and compound (D), respectively] were producedin the same manner from the corresponding compounds (II).

Compounds (I) R¹ R² R³ R⁵ R⁴ Melting point (° C.) (B) H H CH₃ H OCH₂CF₃178-182 (decomp.) (C) H H H H OCH₂CH₂CH₃ 123-125 (decomp.) (D) H H CH₃ HOCH₂CH₂CH₃ 81-83

EXAMPLE 1

Of the components given below, the compound (A), magnesium hydroxide,L-cysteine, corn starch and lactose were mixed together, thenmicrocrystalline cellulose, light silicic anhydride and magnesiumstearate, each in half the intended amount, were added. After sufficientadmixing, the mixture was compression-molded on a dry granulator (rollercompactor; Freund, Japan. The compressed mass was ground in a mortar,the resultant granular mass was passed through a round sieve (16 mesh).The remaining portions of microcrystalline cellulose, light silicicanhydride and magnesium stearate were added to the sieved mass and,after admixing, the whole mixture was made up into tablets each weighing250 mg on a rotary tableting machine (Kikusui Seisakusho, Japan).

Composition Per Tablet:

Compound (A) 50 mg Magnesium hydroxide 30 mg L-Cysteine 20 mg Cornstarch 20 mg Lactose 65.2 mg Microcrystalline cellulose 60 mg Lightsilicic anhydride 1.8 mg Magnesium stearate 3.0 mg Total 250.0 mg

EXAMPLE 2

Tablets were produced in the same manner as in Example 1 except thatomeprazole (Note) was used instead of the compound (A).

Note:5-Methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]benzimidazole

EXAMPLE 3

Of the components given below, the compound (B), precipitated calciumcarbonate, corn starch, lactose and hydroxypropylcellulose were mixedtogether, water was added, and the mixture was kneaded, then dried invacuum at 40° C. for 16 hours, ground in a mortar and passed through a16-mesh sieve to give granules. To this was added magnesium stearate andthe resultant mixture was made up into tablets each weighing 200 mg on arotary tableting machine (Kikusui Seisakusho, Japan).

Composition Per Tablet:

Compound (B) 30 mg Precipitated calcium carbonate 50 mg Corn starch 40mg Lactose 73.4 mg Hydroxypropylcellulose 6 mg Magnesium stearate 0.6 mgWater (0.05 ml) Total 200.0 mg

EXAMPLE 4

Tablets were produced in the same manner as in Example 3 except thattimoprazole (Note) was used instead of the compound (B).

Note: 2-[(2-Pyridyl)methylsulfinyl]benzimidazole

EXAMPLE 5

The ingredients given below were mixed well in the porportions givenbelow, water was added, and the mixture was kneaded and granulated in anextruder granulator (Kikusui Seisakusho;screen size 1.0 mm ⊙). Thegranules were immediately converted to spherical form in a spheronizer(Fuji Powder's Marumerizer, Japan; 1,000 rpm). The spherical granuleswere then dried under vacuum at 40° C. for 16 hours and passed throughround sieves to give 12- to 42-mesh granules.

Composition Per 200 mg of Granules

Compound (B) 30 mg Heavy magnesium carbonate 20 mg Corn starch 80 mgMicrocrystalline cellulose 20 mg Carboxymethylcellulose calcium 10 mgHydroxypropylcellulose 10 mg Pluronic F68 4 mg Lactose 26 mg Water (0.1ml) Total 200 mg

EXAMPLE 6

Granules were produced in the same manner as in Example 5 except thatthe compound (D) was used instead of the compound (B).

EXAMPLE 7

Enteric granules were produced by coating the granules obtained inExample 3 with an enteric coating composition specified below using afluidized bed granulator (Okawara, Japan) under conditions such that theinlet air temperature was 50° C. and the granule temperature was 40° C.No. 1 hard capsules were filled with the enteric granules thus obtainedin an amount of 260 mg per capsule using a capsule filling machine(Parke-Davis, U.S.A.).

Enteric Coating Composition:

Enteric coating composition: Eudragit L-30D 138 mg (solids 41.4 mg) Talc4.1 mg Polyethylene glycol 6000 12.4 mg Tween 80 2.1 mg Water 276 μlComposition of enteric granules: Granules of Example 5 200 mg Entericcoat 60 mg Total 260 mg Composition per capsule: Enteric granules 260 mgNo. 1 hard capsule 76 mg Total 336 mg

EXAMPLE 8

Of the components given below, the compound (B), magunesium carbonate,socrose, corn starch and crystalline cellulose were thoroughly mixedtogether to obtain dusting powder.

Nonpareils were put on a centrifugal fluidized coating-granulatar(CF-360 Freund, Japan) and then coated with the dusting powder asdescribed above, while spraying hydroxypropylcellulose solution [4%(w/w)], to give spherical granules. The spherical granules were dried invacuum at 40° C. for 16 hours and then passed through round sieves togive 12 to 32-mesh granules.

Composition Per 190 mg of Granules:

Nonpareil 75 mg Compound (B) 15 mg Magnesium carbonate 15 mg Sucrose 29mg Corn starch 27 mg Crystalline cellulose 27 mg Hydroxypropylcellulose2 mg [Hydroxypropoxy group content: 53.4-77.5%] Water (0.05 ml) Total190 mg

EXAMPLE 9

Enteric granules were produced by coating the granules obtained inExample 8 with an enteric coatig composition specified below usig afluidized bed granulator (Okawara, Japan) under conditions such thatinlet air temperature was 50° C. and the granule temperature was 40° C.No. 2 hard capsules were filled with the enteric granules thus obtainedin an amount of 240 mg per capsule using a capsule filling machine(Parke-Davis, USA).

Enteric Coating Composition:

Enteric coating composition: Eudragit L-30D 104.7 mg (solids 31.4 mg)Talc 9.6 mg Polyethylene glycol 6000 3.2 mg Tween 80 1.6 mg Titaniumoxide 4.2 mg Water (220 μl) Composition of enteric granules: Granules ofExample 8 190 mg Enteric coat 50 mg Total 240 mg Composition percapsule: Enteric granules 240 mg No. 2 hard capsule 65 mg Total 305 mg

EXAMPLE 10

Composition 1: Compound (B) 450 g Magnesium carbonate 450 g Sucrose 450g Corn starch 450 g Low substituted hydroxypropylcellulose 450 g(Hydroxypropoxy group content: 10.0—13.0% (w/w), average particle size:no more than 30 μm] Composition 2: Sucrose 420 g Corn starch 360 g Lowsubstituted hydroxypropylcellulose 360 g (Hydroxypropoxy group content:10.0-13.0% (w/w), average particle size: no more than 30 μm]

Ingredients of the above composition 1 and composition 2 were thoroughlymixed together to obtain dusting powder 1 and dusting powder 2,respectively.

2250 g of nonpareils were put on a centrifugal fluidized coatinggranulatar (CF-360 Freund, Japan) and then coated with the dustingpowder 1, then with the dusting powder 2, while spraying 60 g ofhydroxypropylcellulose in water (2000 ml) to give spherical granules.

The spherical granules were dried in vacuum at 40° C. for 16 hours andthen passed through round sieve to give 12 to 32-mesh granules.

EXAMPLE 11

Enteric granules were produced by coating 3800 g of the granulesobtained in Example 10 with an enteric coating composition specifiedbelow using a fluidized bed granulatar (Okawara, Japan) under conditionssuch that inlet air temperature was 50° C. and the granule temperaturewas 40° C. No. 2 hard capsules were filled with the enteric granulesthus obtained in an amount of 240 mg per capsule using a filling machine(Parke-Davis, USA).

Enteric Coating Composition:

Eudragit L30D-55 628 g Talc 192 g Polyethylene glycol 6000 64 g Titaniumoxide 64 g Tween 80 32 g Water 4400 ml

Composition Per Capsule:

Enteric granules 240 mg No. 2 hard capsule 65 mg

EXPERIMENTAL EXAMPLE 1a

The ingredients given below were mixed well in the proportions givenbelow, water was added, and the mixture was kneaded and granulated in anextruder granulator (Kikusui Seisakusho; screen size 1.0 mm φ). Thegranules were immediately converted to spherical form in a spheronizer(Fuji Powder's Marumerizer, Japan; 1,000 rpm). The spherical granuleswere then dried under vacuum at 40° C. for 16 hours and passed throughround sieves to give 12- to 42-mesh granules.

Composition Per 200 mg of Granules

Compound (B) 30 mg Heavy magnesium carbonate 20 mg Corn starch 80 mgMicrocrystalline cellulose 20 mg Carboxymethylcellulose calcium 10 mgHydroxypropylcellulose 10 mg Pluronic F68 4 mg Lactose 26 mg Water (0.1ml) Total 200 mg

After storage at 50° C. and 75% RH for 1 week, the granules wereobserved for changes in appearance. The granules of this example showedno change in appearance.

EXPERIMENT EXAMPLE 1b

The ingredients given below were mixed well in the proportions givenbelow, water was added, and the mixture was kneaded and granulated in anextruder granulator (Kikusui Seisakusho; screen size 1.0 mm φ). Thegranules were immediately converted to spherical form in a spheronizer(Fuji Powder's Marumerizer, Japan; 1,000 rpm). The spherical granuleswere then dried under vacuum at 40° C. for 16 hours and passed throughround sieves to give 12- to 42-mesh granules.

Composition Per 200 mg of Granules

Compound (B) 30 mg Magnesium Oxide 20 mg Corn starch 80 mgMicrocrystalline cellulose 20 mg Carboxymethylcellulose calcium 10 mgHydroxypropylcellulose 10 mg Pluronic F68 4 mg Lactose 26 mg Water (0.1ml) Total 200 mg

After storage at 50° C. and 75% RH for 1 week, the granules wereobserved for changes in appearance. The granules of this example showedno change in appearance.

EXPERIMENTAL EXAMPLE 1c

The ingredients given below were mixed well in the proportions givenbelow, water was added, and the mixture was kneaded and granulated in anextruder granulator (Kikusui Seisakusho; screen size 1.0 mm φ). Thegranules were immediately converted to spherical form in a spheronizer(Fuji Powder's Marumerizer, Japan; 1,000 rpm). The spherical granuleswere then dried under vacuum at 40° C. for 16 hours and passed throughround sieves to give 12- to 42-mesh granules.

Composition Per 200 mg of Granules

Compound (B) 30 mg Magnesium Metasilicate Aluminate 20 mg Corn starch 80mg Microcrystalline cellulose 20 mg Carboxymethylcellulose calcium 10 mgHydroxypropylcellulose 10 mg Pluronic F68 4 mg Lactose 26 mg Water (0.1ml) Total 200 mg

After storage at 50° C. and 75% RH for 1 week, the granules wereobserved for changes in appearance. The granules of this example showedno change in appearance.

EXPERIMENTAL EXAMPLE 1d

The ingredients given below were mixed well in the proportions givenbelow, water was added, and the mixture was kneaded and granulated in anextruder granulator (Kikusui Seisakusho; screen size 1.0 mm φ). Thegranules were immediately converted to spherical form in a spheronizer(Fuji Powder's Marumerizer, Japan; 1,000 rpm). The spherical granuleswere then dried under vacuum at 40° C. for 16 hours and passed throughround sieves to give 12- to 42-mesh granules.

Composition Per 200 mg of Granules

Compound (B) 30 mg Synthetic Hydrotalcite 20 mg Corn starch 80 mgMicrocrystalline cellulose 20 mg Carboxymethylcellulose calcium 10 mgHydroxypropylcellulose 10 mg Pluronic F68 4 mg Lactose 26 mg Water (0.1ml) Total 200 mg

After storage at 50° C. and 75% RH for 1 week, the granules wereobserved for changes in appearance. The granules of this example showedno change in appearance.

EXPERIMENTAL EXAMPLE 1e

The ingredients given below were mixed well in the proportions givenbelow, water was added, and the mixture was kneaded and granulated in anextruder granulator (Kikusui Seisakusho; screen size 1.0 mm φ). Thegranules were immediately converted to spherical form in a spheronizer(Fuji Powder's Marumerizer, Japan; 1,000 rpm). The spherical granuleswere then dried under vacuum at 40° C. for 16 hours and passed throughround sieves to give 12- to 42-mesh granules.

Composition Per 200 mg of Granules

Compound (B) 30 mg Aluminum magnesium hydroxide 20 mg Corn starch 80 mgMicrocrystalline cellulose 20 mg Carboxymethylcellulose calcium 10 mgHydroxypropylcellulose 10 mg Pluronic F68 4 mg Lactose 26 mg Water (0.1ml) Total 200 mg

After storage at 50° C. and 75% RH for 1 week, the granules wereobserved for changes in appearance. The granules of this example showedno change in appearance.

EXPERIMENTAL EXAMPLE 1f

The ingredients given below were mixed well in the proportions givenbelow, water was added, and the mixture was kneaded and granulated in anextruder granulator (Kikusui Seisakusho; screen size 1.0 mm φ). Thegranules were immediately converted to spherical form in a spheronizer(Fuji Powder's Marumerizer, Japan; 1,000 rpm). The spherical granuleswere then dried under vacuum at 40° C. for 16 hours and passed throughround sieves to give 12- to 42-mesh granules.

Composition Per 200 mg of Granules

Compound (B) 30 mg Magnesium silicate 20 mg Corn starch 80 mgMicrocrystalline cellulose 20 mg Carboxymethylcellulose calcium 10 mgHydroxypropylcellulose 10 mg Pluronic F68 4 mg Lactose 26 mg Water (0.1ml) Total 200 mg

After storage at 50° C. and 75% RH for 1 week, the granules wereobserved for changes in appearance. The granules of this example showedno change in appearance.

EXPERIMENTAL EXAMPLE 1g

The ingredients given below were mixed well in the proportions givenbelow, water was added, and the mixture was kneaded and granulated in anextruder granulator (Kikusui Seisakusho; screen size 1.0 mm φ). Thegranules were immediately converted to spherical form in a spheronizer(Fuji Powder's Marumerizer, Japan; 1,000 rpm). The spherical granuleswere then dried under vacuum at 40° C. for 16 hours and passed throughround sieves to give 12- to 42-mesh granules.

Composition Per 200 mg of Granules

Compound (B) 30 mg Precipitated calcium carbonate 20 mg Corn starch 80mg Microcrystalline cellulose 20 mg Carboxymethylcellulose calcium 10 mgHydroxypropylcellulose 10 mg Pluronic F68 4 mg Lactose 26 mg Water (0.1ml) Total 200 mg

After storage at 50° C. and 75% RH for 1 week, the granules wereobserved for changes in appearance. The granules of this example showedno change in appearance.

EXPERIMENTAL EXAMPLE 1h

The ingredients given below were mixed well in the proportions givenbelow, water was added, and the mixture was kneaded and granulated in anextruder granulator (Kikusui Seisakusho; screen size 1.0 mm φ). Thegranules were immediately converted to spherical form in a spheronizer(Fuji Powder's Marumerizer, Japan; 1,000 rpm). The spherical granuleswere then dried under vacuum at 40° C. for 16 hours and passed throughround sieves to give 12- to 42-mesh granules.

Composition Per 200 mg of Granules

Compound (B) 30 mg Magnesium hydroxide 20 mg Corn starch 80 mgMicrocrystalline cellulose 20 mg Carboxymethylcellulose calcium 10 mgHydroxypropylcellulose 10 mg Pluronic F68 4 mg Lactose 26 mg Water (0.1ml) Total 200 mg

After storage at 50° C. and 75% RH for 1 week, the granules wereobserved for changes in appearance. The granules of this example showedno change in appearance.

EXPERIMENTAL EXAMPLE 1i

The ingredients given below were mixed well in the proportions givenbelow, water was added, and the mixture was kneaded and granulated in anextruder granulator (Kikusui Seisakusho; screen size 1.0 mm φ). Thegranules were immediately converted to spherical form in a spheronizer(Fuji Powder's Marumerizer, Japan; 1,000 rpm). The spherical granuleswere then dried under vacuum at 40° C. for 16 hours and passed throughround sieves to give 12- to 42-mesh granules.

Composition Per 200 mg of Granules

Compound (B) 30 mg Sodium carbonate 20 mg Corn starch 80 mgMicrocrystalline cellulose 20 mg Carboxymethylcellulose calcium 10 mgHydroxypropylcellulose 10 mg Pluronic F68 4 mg Lactose 26 mg Water (0.1ml) Total 200 mg

After storage at 50° C. and 75% RH for 1 week, the granules wereobserved for changes in appearance. The granules of this example showeda moderate change in appearance to yellow.

EXPERIMENTAL EXAMPLE 1j

The ingredients given below were mixed well in the proportions givenbelow, water was added, and the mixture was kneaded and granulated in anextruder granulator (Kikusui Seisakusho; screen size 1.0 mm φ). Thegranules were immediately converted to spherical form in a spheronizer(Fuji Powder's Marumerizer, Japan; 1,000 rpm). The spherical granuleswere then dried under vacuum at 40° C. for 16 hours and passed throughround sieves to give 12- to 42-mesh granules.

Composition Per 200 mg of Granules

Compound (B) 30 mg Potassium carbonate 20 mg Corn starch 80 mgMicrocrystalline cellulose 20 mg Carboxymethylcellulose calcium 10 mgHydroxypropylcellulose 10 mg Pluronic F68 4 mg Lactose 26 mg Water (0.1ml) Total 200 mg

After storage at 50° C. and 75% RH for 1 week, the granules wereobserved for changes in appearance. The granules of this example showeda moderate change in appearance to yellow.

EXPERIMENTAL EXAMPLE 1k

The ingredients given below were mixed well in the proportions givenbelow, water was added, and the mixture was kneaded and granulated in anextruder granulator (Kikusui Seisakusho; screen size 1.0 mm φ). Thegranules were immediately converted to spherical form in a spheronizer(Fuji Powder's Marumerizer, Japan; 1,000 rpm). The spherical granuleswere then dried under vacuum at 40° C. for 16 hours and passed throughround sieves to give 12- to 42-mesh granules.

Composition Per 200 mg of Granules

Compound (B) 30 mg Sodium hydrogen carbonate 20 mg Corn starch 80 mgMicrocrystalline cellulose 20 mg Carboxymethylcellulose calcium 10 mgHydroxypropylcellulose 10 mg Pluronic F68 4 mg Lactose 26 mg Water (0.1ml) Total 200 mg

After storage at 50° C. and 75% RH for 1 week, the granules wereobserved for changes in appearance. The granules of this example showeda moderate change in appearance to yellow.

EXPERIMENTAL EXAMPLE 1l

The ingredients given below were mixed well in the proportions givenbelow, water was added, and the mixture was kneaded and granulated in anextruder granulator (Kikusui Seisakusho; screen size 1.0 mm φ). Thegranules were immediately converted to spherical form in a spheronizer(Fuji Powder's Marumerizer, Japan; 1,000 rpm). The spherical granuleswere then dried under vacuum at 40° C. for 16 hours and passed throughround sieves to give 12- to 42-mesh granules.

Composition Per 200 mg of Granules

Compound (B) 30 mg Magnesium chloride 20 mg Corn starch 80 mgMicrocrystalline cellulose 20 mg Carboxymethylcellulose calcium 10 mgHydroxypropylcellulose 10 mg Pluronic F68 4 mg Lactose 26 mg Water (0.1ml) Total 200 mg

After storage at 50° C. and 75% RH for 1 week, the granules wereobserved for changes in appearance. The granules of this example showeda severe change in appearance, to violet.

EXPERIMENTAL EXAMPLE 1m

The ingredients given below were mixed well in the proportions givenbelow, water was added, and the mixture was kneaded and granulated in anextruder granulator (Kikusui Seisakusho; screen size 1.0 mm φ). Thegranules were immediately converted to spherical form in a spheronizer(Fuji Powder's Marumerizer, Japan; 1,000 rpm). The spherical granuleswere then dried under vacuum at 40° C. for 16 hours and passed throughround sieves to give 12- to 42-mesh granules.

Composition Per 200 mg of Granules

Compound (B) 30 mg Magnesium sulfate 20 mg Corn starch 80 mgMicrocrystalline cellulose 20 mg Carboxymethylcellulose calcium 10 mgHydroxypropylcellulose 10 mg Pluronic F68 4 mg Lactose 26 mg Water (0.1ml) Total 200 mg

After storage at 50° C. and 75% RH for 1 week, the granules wereobserved for changes in appearance. The granules of this example showeda severe change in appearance, to violet.

EXPERIMENTAL EXAMPLE 1n

The ingredients given below were mixed well in the proportions givenbelow, water was added, and the mixture was kneaded and granulated in anextruder granulator (Kikusui Seisakusho; screen size 1.0 mm φ). Thegranules were immediately converted to spherical form in a spheronizer(Fuji Powder's Marumerizer, Japan; 1,000 rpm). The spherical granuleswere then dried under vacuum at 40° C. for 16 hours and passed throughround sieves to give 12- to 42-mesh granules.

Composition Per 200 mg of Granules

Compound (B) 30 mg Calcium chloride 20 mg Corn starch 80 mgMicrocrystalline cellulose 20 mg Carboxymethylcellulose calcium 10 mgHydroxypropylcellulose 10 mg Pluronic F68 4 mg Lactose 26 mg Water (0.1ml) Total 200 mg

After storage at 50° C. and 75% RH for 1 week, the granules wereobserved for changes in appearance. The granules of this example showeda severe change in appearance, to violet.

EXPERIMENTAL EXAMPLE 1o

The ingredients given below were mixed well in the proportions givenbelow, water was added, and the mixture was kneaded and granulated in anextruder granulator (Kikusui Seisakusho; screen size 1.0 mm φ). Thegranules were immediately converted to spherical form in a spheronizer(Fuji Powder's Marumerizer, Japan; 1,000 rpm). The spherical granuleswere then dried under vacuum at 40° C. for 16 hours and passed throughround sieves to give 12- to 42-mesh granules.

Composition Per 200 mg of Granules

Compound (B) 30 mg aluminum silicate 20 mg Corn starch 80 mgMicrocrystalline cellulose 20 mg Carboxymethylcellulose calcium 10 mgHydroxypropylcellulose 10 mg Pluronic F68 4 mg Lactose 26 mg Water (0.1ml) Total 200 mg

After storage at 50° C. and 75% RH for 1 week, the granules wereobserved for changes in appearance. The granules of this example showeda moderate change in appearance, to violet.

EXPERIMENTAL EXAMPLE 1p

The ingredients given below were mixed well in the proportions givenbelow, water was added, and the mixture was kneaded and granulated in anextruder granulator (Kikusui Seisakusho; screen size 1.0 mm φ). Thegranules were immediately converted to spherical form in a spheronizer(Fuji Powder's Marumerizer, Japan; 1,000 rpm). The spherical granuleswere then dried under vacuum at 40° C. for 16 hours and passed throughround sieves to give 12- to 42-mesh granules.

Composition Per 200 mg of Granules

Compound (B) 30 mg Corn starch 80 mg Microcrystalline cellulose 20 mgCarboxymethylcellulose calcium 10 mg Hydroxypropylcellulose 10 mgPluronic F68 4 mg Lactose 46 mg Water (0.1 ml) Total 200 mg

After storage at 50° C. and 75% RH for 1 week, the granules wereobserved for changes in appearance. The granules of this example showeda severe change in appearance, to violet.

EXPERIMENTAL EXAMPLE 2

Granules were produced in the same manner as in Example 5 except thatthe compound (A), the compound (C), the compound (D), omeprazole ortimoprazole was used instead of the compound (B). After storage at 50°C. and 75% RH for 1 week, they were observed for changes in appearance.As a control to each composition, granules were also produced in thesame manner except that lactose was used instead of heavy magnesiumcarbonate and stored under the same conditions.

Changes in appear- ance after 1 week Compound Additive at 50° C. and 75%RH Compound (A) Invention: Heavy magnesium − carbonate Control: Lactose++ Omeprazole Invention: Heavy magnesium − carbonate Control: Lactose ++Timoprazole Invention: Heavy magnesium − carbonate Control: Lactose ++Compound (C) Invention: Heavy magnesium − carbonate Control: Lactose ++Compound (D) Invention: Heavy magnesium − carbonate Control: Lactose ++Notes: −: No changes ++: Severely

As is evident from the above results, the pharmaceutical compositions ofthe invention were all stable whether the active ingredient was thecompound (A) omeprazole, timoprazole, the compound (C) or the compound(D).

EXPERIMENTAL EXAMPLE 3

Pharmaceutical compositions were produced in the same manner as inExamples 3 and 5 except that different basic inorganic Mg or Ca saltswere used or that lactose was used as a control, and Example 6. Afterstrage at 50° C. and 75% RH for 1 week or at 40° C. for 6 months, thecompositions were observed for changes in appearance and for activeingredient content (residual percentage).

TABLE 2 50° C., 75% 40° C., Additive Initial RH, 1 week 6 months Tabletsmade by the procedure of Example 3 Invention Heavy magnesium AppearanceWhite No change No change carbonate Content 100% 98.0% 99.5%Precipitated calcium Appearance White No change No change carbonateContent 100% 97.4% 96.5% Magnesium silicate Appearance White No changeNo change Content 100% 94.5% 95.0% Control No addition (lactose)Appearance Pale violet Dark violet Dark violet Content 100% 73.5% 82.1%Granudles made by the procedure of Example 5 Invention Heavy magnesiumAppearance White No change No change carbonate Content 100% 98.2% 99.1%Precipitate calcium Appearance White No change No change carbonateContent 100% 97.2% 98.6% Magnesium oxide Appearance White No change Nochange Content 100% 99.4% 99.0% Control No addition (lactose) AppearancePale violet Dark violet Dark violet Content 100% 84.2% 89.4% Capsules ofExample 7 Invention Heavy magnesium Appearance White No change No changecarbonate Content 100% 98.4% 99.1%

The above results clearly indicate that the compositions of theinvention show no changes in appearance at all and are stable in termsof the active ingredient content.

We claim:
 1. A stabilized pharmaceutical composition for the inhibitionof gastric acid secretion, comprising an effective amount of abenzimidazole compound of the formula (I)

wherein R¹ is hydrogen, alkyl, halogen, cyano, carboxy, carboalkoxy,carboalkoxyalkyl, carbamoyl, carbamoylalkyl, hydroxy, alkoxyhydroxyalkyl, trifluoromethyl, acyl carbamoyloxy, nitro, acyloxy, aryl,aryloxy, alkylthio or alkylsulfinyl; R² is hydrogen, alkyl, acyl,carboalkoxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,alkylcarbonylmethyl, alkoxycarbonylmethyl or alkylsulfonyl; R³ and R⁵are the same or different and each is hydrogen, alkyl, alkoxy oralkoxyalkoxy; R⁴ is hydrogen, alkyl, alkoxy which may optionally befluorinated, or alkoxyalkoxy; and m is an integer from 0 to 4, or aderivative thereof or salt thereof having a gastric acid secretioninhibitory property, and a basic inorganic salt stabilizing agent,wherein the stabilizing agent is a basic inorganic salt of at least oneselected from the group consisting of magnesium, calcium, potassium, andsodium and the stabilizing agent is homogenously admixed with thecompound of the formula (I) in an effective amount to provide stabilityto the compound of the formula (I).
 2. A composition of claim 1, whereinthe basic inorganic salt stabilizing agent is a basic inorganic salt ofmagnesium or calcium.
 3. A composition of claim 1, wherein the basicinorganic salt stabilizing agent is a basic inorganic salt of sodium. 4.A composition of claim 1, wherein the basic inorganic salt stabilizingagent is a basic inorganic salt of potassium.